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Citations to this article

Matriptase-mediated cleavage of EpCAM destabilizes claudins and dysregulates intestinal epithelial homeostasis
Chuan-Jin Wu, … , Sohshi Morimura, Mark C. Udey
Chuan-Jin Wu, … , Sohshi Morimura, Mark C. Udey
Published January 17, 2017
Citation Information: J Clin Invest. 2017;127(2):623-634. https://doi.org/10.1172/JCI88428.
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Research Article Cell biology Gastroenterology Article has an altmetric score of 2

Matriptase-mediated cleavage of EpCAM destabilizes claudins and dysregulates intestinal epithelial homeostasis

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Abstract

Congenital tufting enteropathy (CTE) is a severe autosomal recessive human diarrheal disorder with characteristic intestinal epithelial dysplasia. CTE can be caused by mutations in genes encoding EpCAM, a putative adhesion molecule, and HAI-2, a cell surface protease inhibitor. A similar phenotype occurs in mice whose intestinal epithelial cells (IECs) fail to express the tight junction–associated protein claudin-7. EpCAM stabilizes claudin-7 in IECs, and HAI-2 regulates the cell surface serine protease matriptase, a known modifier of intestinal epithelial physiology. Therefore, we hypothesized that HAI-2, matriptase, EpCAM, and claudin-7 were functionally linked. Herein we have demonstrated that active matriptase cleaves EpCAM after Arg80 and that loss of HAI-2 in IECs led to unrestrained matriptase activity and efficient cleavage of EpCAM. Cleavage of EpCAM decreased its ability to associate with claudin-7 and targeted it for internalization and lysosomal degradation in conjunction with claudin-7. CTE-associated HAI-2 mutant proteins exhibited reduced ability to inhibit matriptase and also failed to efficiently stabilize claudin-7 in IECs. These results identify EpCAM as a substrate of matriptase and link HAI-2, matriptase, EpCAM, and claudin-7 in a functionally important pathway that causes disease when it is dysregulated.

Authors

Chuan-Jin Wu, Xu Feng, Michael Lu, Sohshi Morimura, Mark C. Udey

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Total citations by year

Year: 2024 2023 2022 2021 2020 2019 2018 2017 Total
Citations: 2 3 4 9 15 3 8 3 47
Citation information
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Citations to this article (47)

Title and authors Publication Year
SPINT2 mutations in the Kunitz domain 2 found in SCSD patients inactivate HAI-2 as prostasin inhibitor via abnormal protein folding and N-glycosylation
Huang N, Wang Q, Bernard RB, Chen CY, Hu JM, Wang JK, Chan KS, Johnson MD, Lin CY
Human Molecular Genetics 2024
Regulation of the Function and Expression of EpCAM
Xiao D, Xiong M, Wang X, Lyu M, Sun H, Cui Y, Chen C, Jiang Z, Sun F
Biomedicines 2024
Type II Transmembrane Serine Proteases as Modulators in Adipose Tissue Phenotype and Function
Wu Q, Li S, Zhang X, Dong N
Biomedicines 2023
Early-onset tufting enteropathy in HAI-2-deficient mice is independent of matriptase-mediated cleavage of EpCAM.
Szabo R, Kawaguchi M, Kataoka H, Bugge TH
Development (Cambridge, England) 2023
Matriptase-2 regulates iron homeostasis primarily by setting the basal levels of hepatic hepcidin expression through a nonproteolytic mechanism
Enns CA, Weiskopf T, Zhang RH, Wu J, Jue S, Kawaguchi M, Kataoka H, Zhang AS
The Journal of biological chemistry 2023
EPCAM and TROP2 share a role in claudin stabilization and development of intestinal and extraintestinal epithelia in mice
Szabo R, Ward JM, Artunc F, Bugge TH
Biology Open 2022
Understanding the versatile roles and applications of EpCAM in cancers: from bench to bedside.
Liu Y, Wang Y, Sun S, Chen Z, Xiang S, Ding Z, Huang Z, Zhang B
Experimental Hematology and Oncology 2022
EpCAM proteolysis and release of complexed claudin-7 repair and maintain the tight junction barrier
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The Journal of Cell Biology 2022
The genetics of monogenic intestinal epithelial disorders.
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Human Genetics 2022
Intestinal immunoregulation: lessons from human mendelian diseases
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Mucosal Immunology 2021
EpCAM (CD326) Regulates Intestinal Epithelial Integrity and Stem Cells via Rho-Associated Kinase
T Ouchi, S Morimura, LE Dow, H Miyoshi, MC Udey
Cells 2021
The Kunitz-type serine protease inhibitor Spint2 is required for cellular cohesion, coordinated cell migration and cell survival during zebrafish hatching gland development
J Hatzold, H Wessendorf, HM Pogoda, W Bloch, M Hammerschmidt
Developmental Biology 2021
Three Novel EPCAM Variants Causing Tufting Enteropathy in Three Families
HA Civan, C Leitner, I Östreicher, AM Schneider, M Cremer, JA Mayr, R Rossi, T Müller, AR Janecke
Children 2021
Targeted HAI-2 deletion causes excessive proteolysis with prolonged active prostasin and depletion of HAI-1 monomer in intestinal but not epidermal epithelial cells
RB Barndt, MJ Lee, N Huang, DD Lu, SC Lee, PW Du, CC Chang, PF Tsai, YS Huang, HM Chang, JK Wang, CH Lai, MD Johnson, CY Lin
Human Molecular Genetics 2021
Aberrant Epithelial Differentiation Contributes to Pathogenesis in a Murine Model of Congenital Tufting Enteropathy
B Das, K Okamoto, J Rabalais, JA Young, KE Barrett, M Sivagnanam
CMGH Cellular and Molecular Gastroenterology and Hepatology 2021
Structural insights into the cis and trans assembly of human trophoblast cell surface antigen 2
M Sun, H Zhang, M Jiang, Y Chai, J Qi, GF Gao, S Tan
iScience 2021
Interactome analysis reveals endocytosis and membrane recycling of EpCAM during differentiation of embryonic stem cells and carcinoma cells
M Pan, V Kohlbauer, AB Soares, H Schinke, Y Huang, G Kranz, T Quadt, M Hachmeister, O Gires
iScience 2021
Trop2 Forms a Stable Dimer with Significant Structural Differences within the Membrane-Distal Region as Compared to EpCAM
M Pavšič
International journal of molecular sciences 2021
Tufting Enteropathy: A Review of Clinical and Histological Presentation, Etiology, Management, and Outcome
C Cai, Y Chen, X Chen, F Ji
Gastroenterology Research and Practice 2020
Expression of a TMC6-TMC8-CIB1 heterotrimeric complex in lymphocytes is regulated by each of the components
CJ Wu, X Li, CL Sommers, K Kurima, S Huh, G Bugos, L Dong, W Li, AJ Griffith, LE Samelson
The Journal of biological chemistry 2020
Trop2: Jack of All Trades, Master of None
S Lenárt, P Lenárt, J Šmarda, J Remšík, K Souček, P Beneš
Cancers 2020
Congenital Tufting Enteropathy-Associated Mutant of Epithelial Cell Adhesion Molecule Activates the Unfolded Protein Response in a Murine Model of the Disease
B Das, K Okamoto, J Rabalais, RR Marchelletta, KE Barrett, S Das, M Niwa, M Sivagnanam
Cells 2020
Expression and function of epithelial cell adhesion molecule EpCAM: where are we after 40 years?
O Gires, M Pan, H Schinke, M Canis, PA Baeuerle
Cancer and Metastasis Reviews 2020
Dysregulation of Type II Transmembrane Serine Proteases and Ligand-Dependent Activation of MET in Urological Cancers
S Mukai, K Yamasaki, M Fujii, T Nagai, N Terada, H Kataoka, T Kamoto
International journal of molecular sciences 2020
Current View on EpCAM Structural Biology
A Gaber, B Lenarčič, M Pavšič
Cells 2020
Matriptase processing of APLP1 ectodomain alters its homodimerization
E Lanchec, A Désilets, F Béliveau, C Fontaine-Carbonneau, A Laniel, R Leduc, C Lavoie
Scientific Reports 2020
Amelioration of Congenital Tufting Enteropathy in EpCAM (TROP1)-Deficient Mice via Heterotopic Expression of TROP2 in Intestinal Epithelial Cells
G Nakato, S Morimura, M Lu, X Feng, C Wu, MC Udey
Cells 2020
EpCAM as Modulator of Tissue Plasticity
F Fagotto
Cells 2020
Membrane-anchored serine proteases as regulators of epithelial function
R Szabo, TH Bugge
Biochemical Society Transactions 2020
Characterization of CD147, CA9, and CD70 as Tumor-Specific Markers on Extracellular Vesicles in Clear Cell Renal Cell Carcinoma
D Himbert, P Zeuschner, H Ayoubian, J Heinzelmann, M Stöckle, K Junker
Diagnostics 2020
SPINT2 inhibits proteases involved in activation of both influenza viruses and metapneumoviruses
MR Straus, JT Kinder, M Segall, RE Dutch, GR Whittaker
Virology 2020
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B Das, M Sivagnanam
Journal of Clinical Medicine 2020
Matriptase Cleaves EpCAM and TROP2 in Keratinocytes, Destabilizing Both Proteins and Associated Claudins
CJ Wu, M Lu, X Feng, G Nakato, MC Udey
Cells 2020
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Hepatocyte growth factor activator inhibitor-2 stabilizes Epcam and maintains epithelial organization in the mouse intestine
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2019
Matriptase drives early-onset intestinal failure in a mouse model of congenital tufting enteropathy
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Gastroenterology 2018
Protease signaling regulates apical cell extrusion, cell contacts, and proliferation in epithelia
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The Journal of Cell Biology 2018
Loss of HAI-2 in mice with decreased prostasin activity leads to an early-onset intestinal failure resembling congenital tufting enteropathy
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PloS one 2018
Dysregulated HAI-2 Plays an Important Role in Renal Cell Carcinoma Bone Metastasis through Ligand-Dependent MET Phosphorylation
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PloS one 2018
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The Journal of biological chemistry 2018
EPCAM mutation update: Variants associated with congenital tufting enteropathy and Lynch syndrome
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